PARP1-Selective Compounds for HR-Deficient Tumor Targeting

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current PARP inhibitors lack selectivity for PARP1, leading to potential off-target effects and reduced efficacy in cancer treatment, particularly in tumors with homologous recombination deficiency (HRD).

Innovation Solution

Development of compounds with high selectivity for PARP1 over PARP2, designed to inhibit PARP1 activity, thereby enhancing therapeutic efficacy in cancers with deficient HR-dependent DNA DSB repair pathways.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current PARP inhibitors are used, then PARP family enzymes are inhibited, but selectivity for PARP1 is insufficient leading to off-target effects

Engineering Contradiction:

Improveselectivity for PARP1VSAvoidoff-target effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent modifies specific local regions of the PARP inhibitor molecule (positions R1, R2, R3, R4, R5 in the chemical structure) to create differential binding affinity. By optimizing substituents at these specific locations, the compound achieves high selectivity for PARP1 while maintaining inhibition activity, thereby reducing off-target effects on other PARP family members.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent systematically varies chemical parameters including substituent types (halogen, alkyl, alkoxy groups), their positions on the aromatic rings, and stereochemistry (R/S configurations). These parameter changes in the molecular structure enable fine-tuning of selectivity for PARP1 over other PARP isoforms, achieving 10-100 fold selectivity ratios.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If non-selective PARP inhibitors are used, then broad PARP family inhibition occurs, but therapeutic efficacy in HR-deficient tumors is reduced

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidbroad PARP family inhibition

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent extracts and isolates the specific molecular interactions required for PARP1 binding by removing or modifying groups that mediate interactions with PARP2 and other isoforms. This selective extraction of binding features enables the inhibitor to target PARP1 specifically, which is the primary driver of efficacy in HR-deficient tumors, without requiring broad family-wide inhibition.

Inventive Principle:

Principle #2Taking out (Extraction)

3Reliability

If PARP1 selectivity is enhanced through molecular modification, then therapeutic index improves, but compound complexity increases

Engineering Contradiction:

Improvetherapeutic indexVSAvoidmolecular complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent implements partial modification of the molecular structure by introducing selective substituents only at critical positions (R1-R5) that influence PARP1 binding, while keeping other portions of the molecule simple and scaffold-based. This partial action approach achieves the necessary selectivity improvement without requiring complete redesign of the entire molecular architecture, thus limiting complexity increase.

Inventive Principle:

Principle #16Partial or excessive action

Data Source

PatentUS20250289814A1Compounds as PARP1 inhibitiors

Publication Date: 2025.09.18 NINGBO NEWBAY TECHNOLOGY DEVELOPMENT CO LTD

AI summary

Disclosed herein is the compounds and pharmaceutically acceptable salts thereof that inhibit the Poly (ADP-ribose) polymerase (PARP) family of enzymes. The present disclosure also relates to the use of these compounds or pharmaceutically acceptable salts thereof in the treatment of diseases.